The field of study called population genetics has played a critical role in the development of modern biology, helping unite Mendelian genetics and Darwinian evolution into one coherent framework. In most genetics classes, though, it typically gets plowed through in a simplified form in a single lecture. I suspect this is because it involves a lot of math, and most biologists like being in the field precisely because it's generally possible to avoid all but the simplest math.

Nevertheless, population genetics has some critical insights to offer in the area of modern genomics, as evidenced by a paper that appeared in this week's edition of Science. Some population geneticists have looked into the results of the search for mutations in genome data. Their conclusion: the human population explosion has led to the appearance of many new, rare mutations in the human population, and it's throwing all the math off, which has some serious implications for medical research.

At the simplest level, population genetics can help us predict how often a mutation should be present in a specific population. Feed its equations things like the population size, how harmful or beneficial the mutation is, the typical mutation rate, and so forth, and it will spit out a nice prediction of what the final frequency of the mutation should be. It nicely demonstrates why even harmful mutations stick around at low levels in a population, even as evolution is doing its best to get rid of them.

The reason the math gets complicated is that the equations describe a population at equilibrium, and most populations aren't. Once you start adjusting for things like genetic drift, population bottlenecks, and migration, the equations all become a lot messier.

Most human populations exhibit just about all of these complications, but the authors focused on one aspect in particular: its rather unusual growth pattern. Over the past 400 generations of humans, it's estimated that the total population has expanded by something on the order of 1,000 fold. Not only that, but the growth has been uneven. The spread of urban centers starting about 3,000 years ago interrupted a period of relatively stable growth, and things like better nutrition, public sanitation, and vaccines have set off a period of even more rapid growth in the last 1,000 years.

Significant population growth is enough to throw a simple population genetics model off. If you have the sort of lopsided growth humans have seen and you adjust for it using a linear pattern of growth, the results will go off pretty badly. To show just how badly, the authors calculated some expected frequencies based on three different models for a European population: no growth, steady growth with bottlenecks, and the same bottlenecks, but with recent exponential growth. For a large population sample, the simple models can be off by as much as 500 percent.

The model they've developed has some pretty significant implications both for current genomic research and for medicine. As far as research goes, the conclusion is pretty simple: even though we have more human genetic samples than ever before, most studies still haven't been able to survey a large enough population to see the influence of the rapidly expanding human population. That's beginning to change, so it's important that the researchers who are doing this work use the appropriate math, or they're going to have a hard time interpreting what they see.

For medicine, the population growth means that there will be a huge abundance of mutations that have arisen in the past few generations, since population genetics won't have time to lose any via genetic drift, or get rid of them through selective pressure. Many of these mutations will be unique, limited to an original founder and their descendants.

For neutral mutations, which don't confer any harm or benefit, a modified population genetics model should work well. But that will fail for harmful mutations, since it assumes these will have been selected against. In reality, most of them will be so new that this won't have had any chance to happen. "Deleterious mutations would likely exhibit an even larger percentage of novel rare variants," the authors note. And that has consequences for our search for factors involved in complex genetic disorders like autism: "The medical implications of an excess of rare genetic variation and increased individual mutational load are of particular interest in light of the limited success of genome-wide association studies at explaining the genetic basis of complex human diseases."

In other words, our search for the causes of complex genetic diseases is going to be complicated by the fact that most of the mutations that cause them will be unique within the population.

With time, we'll have much more genetic data, and these issues will sort themselves out. But for now, it seems that we may be stuck trying to paint a picture of a dynamic human population based on a partial, static snapshot. Viewed that way, it's not much of a surprise that the completion of the human genome hasn't led to an overnight revolution in our understanding of disease.

40 Reader Comments

Not to mention the advance of medical technology. A lot of effort is being put into keeping people alive who, historically, would have died or rendered unable to reproduce by genetic abnormalities. This only exacerbates the issues posited by the article.

You mean upside. When the Bat-Pigeon-Cow flu strikes in 2017, there is now an increasingly high probability that many people will have unexpected resistance since the genetic mutation had not been weeded out by unrelated causes such as starvation, war, or polio.

So basically the prevalence of disorders like autism may not be some new crap in the environment or something else we have done but just be caused by the sheer number of people that are around now and able to reproduce?

So basically the prevalence of disorders like autism may not be some new crap in the environment or something else we have done but just be caused by the sheer number of people that are around now and able to reproduce?

So basically the prevalence of disorders like autism may not be some new crap in the environment or something else we have done but just be caused by the sheer number of people that are around now and able to reproduce?

That also combines with the fact that people are reproducing at a later age (normally precluded by death or war or inability to find a mate) and that genetic health declines with age for both men and women (we haven't been reproducing for long enough for evolution to selectively favor the genes necessary to allow for reproducing at later ages).

So basically the prevalence of disorders like autism may not be some new crap in the environment or something else we have done but just be caused by the sheer number of people that are around now and able to reproduce?

That also combines with the fact that people are reproducing at a later age (normally precluded by death or war or inability to find a mate) and that genetic health declines with age for both men and women (we haven't been reproducing for long enough for evolution to selectively favor the genes necessary to allow for reproducing at later ages).

Add to the fact that society has also grown (for the most part) tolerant and compassionate for these affected people that they no longer have to isolate themselves (and be removed) in such a way that we don't (the general society at large) notice them in our every day interactions.

(This is from a Western/Developed Nation perspective ... I'm sure autistic people will continually face a harsher existence elsewhere in the world)

How many stories have you read about some "crazy loon", "hermit" or "wayward fella" that lived on the outskirts of town or largely kept to themselves? Were there attempts to understand these people one hundred, two hundred or 500 hundred years ago? How many "strange" people were put to death, chidren and adults, in order to "hide" or "purge" them from society? I don't think enough study/research has been put into this phenomenon, so it's easy for misinformed people to say a problem had just sprung up in recent history, like cancer or genetic diseases or mental illness.

Seriously, we were all mutants anyway. Each person can be estimated to have ~ 100 mutations already at birth (and IIRC that has lately been observed as well), and we accumulate more as we go (albeit partially from stem cells and so on).

"In a growing population, individuals average more than two offspring. Every additional offspring increases the chance that a new mutation will be passed on to the next generation. In other words, more people means less genetic drift. As a population grows, new mutations begin to stack up at low frequencies in the population.

This is a very basic point in population genetic theory, and it interacts in a troubling way with the current generation of sequencing technology. Short-read shotgun sequencing yields a high number of false positive mutations, which must be aggressively filtered out of whole genome data. If we don't filter these out, we will arrive at incorrect conclusions about many aspects of human biology."

Presumably the earlier need for ~ 1000 sequenced human genomes for a reasonably representative statistics has to increase.

And Hawks notes that genomics is playing catch up to his own field:

"It's so interesting to me to see human geneticists catching up to where anthropologists have been for a long time. Of course, we wrote about the effects of recent population expansions in 2007, noting the apparent acceleration of positive selection in post-agricultural populations ("Why human evolution accelerated") [2]."

"For neutral mutations, which don't confer any harm or benefit, a modified population genetics model should work well. But that will fail for harmful mutations, since it assumes these will have been selected against. In reality, most of them will be so new that this won't have had any chance to happen. "Deleterious mutations would likely exhibit an even larger percentage of novel rare variants," "

Won't the same be true for beneficial mutations? Why is there only focus on the negative?

We have tried hard as a society/species to remove or mitigate causes of death, whether it is predators, starvation, illness, etc. This reduces selective pressure which might select away harmful mutations.

In addition to this, physical attractiveness is a less important criterion when intelligence/money are frequently thought of as more important criteria for potential mates. Try adding that to the non-linear differential equation and see what happens.

A lot of effort is being put into keeping people alive who, historically, would have died or rendered unable to reproduce by genetic abnormalities. This only exacerbates the issues posited by the article.

Not really, it lessens selective pressures on some deleterious alleles. The proper way to see it is that it is evolution as usual, the environment has changed.

But the modified environment increases population size, so it increases the effects of the article that way.

TheWerewolf wrote:

Read out a person's DNA, run it through emulation to find the mutations, code up some nanites and have them go in and repair or replace. ... Of course, then evolution kind of stops mattering.

Again, no. Change of environment, but sexual recombination and environmental selection effects are still there, as well as epigenetic effects of histones. Consider that sperm cells compete, that ~ 70 % of fertilized eggs dies, and that some developmental effects are too severe to survive the effects of (say, lacking a brain).

And what do you repair against? Sure, you can fix some obvious SNPs (single nucleotide polymorphism). But when you have these new alleles that the article notes, and you can't know if they are good or bad until selection occurred. G(enetic g)ame over!

We have tried hard as a society/species to remove or mitigate causes of death, whether it is predators, starvation, illness, etc. This reduces selective pressure which might select away harmful mutations.

No, selection has _increased in efficiency_ with population size, as the article notes and Hawks research shows (see the link in an earlier comment of mine).

Evolution kicks ass, and it kicks more ass the more ass there is. It's the Hulk of natural processes.

(This is from a Western/Developed Nation perspective ... I'm sure autistic people will continually face a harsher existence elsewhere in the world)

This depends on the intensity of the issues. Also, the west appears to automate more and more of the kinds of tasks that an autistic excels at.

What I was trying to convey was that autism is less of a mystery the more educated people are about it. In a third world country, however, they face hardships driven by ignorance - brought upon them by society through discrimination, incrimination and/or demonization - in reaction to or as a result of their behavior.

(This is from a Western/Developed Nation perspective ... I'm sure autistic people will continually face a harsher existence elsewhere in the world)

This depends on the intensity of the issues. Also, the west appears to automate more and more of the kinds of tasks that an autistic excels at.

What I was trying to convey was that autism is less of a mystery the more educated people are about it. In a third world country, however, they face hardships driven by ignorance - brought upon them by society through discrimination, incrimination and/or demonization - in reaction to or as a result of their behavior.

Not to mention the advance of medical technology. A lot of effort is being put into keeping people alive who, historically, would have died or rendered unable to reproduce by genetic abnormalities. This only exacerbates the issues posited by the article.

People like me, in fact. Time to re-think eugenics perhaps? As someone who would certainly be a target of any eugenics program it would have my vote. Living with life-long chronic diseases is not fun, and it is very hard to justify inflicting that on a child. Do give us our drugs and medical care please, but we mutes really oughtn't to be breeding.

Quote:

...it involves a lot of math, and most biologists like being in the field precisely because it's generally possible to avoid all but the simplest math

Not the first time I've come across a broad and unjustified disparaging smart-arse remark like that from Mr. Timmer. Putting down actual working scientists makes you feel big does it, John? 'Cos obviously working as a science editor in the popular press requires A LOT more high-level maths than working as a field biologist. In any case this attitude is not a good look.

...it involves a lot of math, and most biologists like being in the field precisely because it's generally possible to avoid all but the simplest math

Not the first time I've come across a broad and unjustified disparaging smart-arse remark like that from Mr. Timmer. Putting down actual working scientists makes you feel big does it, John? 'Cos obviously working as a science editor in the popular press requires A LOT more high-level maths than working as a field biologist. In any case this attitude is not a good look.

Why do you see this as an unjustified or disparaging remark? And then follow it up with a genuine ad-hom? From what I understand, it is broadly true that field biology is (traditionally) mercifully light on mathematics and lots of people aren't huge fans of maths. Natural selection would be expected to increase the number of those not fond of maths in this discipline. He's not making a value judgment (or at least I don't read it that way) about advanced maths, he's just stating a fairly straightforward observation. I really didn't get the impression that he thinks field biologists are semi-retarded individuals who only do it because they can't do anything else. Also, you know, lighten up.

Read every babies genetic code. Look for behavior markers. Then tailor their education to best fit their natural abilities.

Those who feel no guilt, have self delusions of grandeur, lack empathy, pathological ability to lie and have ruthless approaches to dealing with situations would become great captains of industry and politicians.

Women who are likely to suffer low self esteem, body dis-morphia, low IQ and a tendency to use mind altering drugs can be given jobs in the sex industry.

Men who are likely to be subservient to the group, high tolerance for pain, high level of stamina and good spatial awareness could become front line troops.

Those with good analytical skills and problem solving abilities, excellent memory retention and recall and focused one track minds could be used to solve complex business/scientific problems.

I'm sure you're starting to see where I'm heading with this.

Why leave it to chance, as it is now. If we follow this approach we become a streamlined society that can out compete all other nations as we are reducing the inefficiency that plague our nation today, where the wrong people are in the wrong jobs. If we could train people to maximise their latent genetic abilities and predisposition our nation could be unstoppable.

If you consider my musings as reprehensible then you're merely denying this is how the current situation is anyway, except with massive inefficiency. Selective screening and tailored education rather than the blanket approach at present would power any nation that employs it far beyond any of it's competitors too afraid to implement what is the only way.

Read every babies genetic code. Look for behavior markers. Then tailor their education to best fit their natural abilities.

Those who feel no guilt, have self delusions of grandeur, lack empathy, pathological ability to lie and have ruthless approaches to dealing with situations would become great captains of industry and politicians.

Women who are likely to suffer low self esteem, body dis-morphia, low IQ and a tendency to use mind altering drugs can be given jobs in the sex industry.

Men who are likely to be subservient to the group, high tolerance for pain, high level of stamina and good spatial awareness could become front line troops.

Those with good analytical skills and problem solving abilities, excellent memory retention and recall and focused one track minds could be used to solve complex business/scientific problems.

I'm sure you're starting to see where I'm heading with this.

Why leave it to chance, as it is now. If we follow this approach we become a streamlined society that can out compete all other nations as we are reducing the inefficiency that plague our nation today, where the wrong people are in the wrong jobs. If we could train people to maximise their latent genetic abilities and predisposition our nation could be unstoppable.

If you consider my musings as reprehensible then you're merely denying this is how the current situation is anyway, except with massive inefficiency. Selective screening and tailored education rather than the blanket approach at present would power any nation that employs it far beyond any of it's competitors too afraid to implement what is the only way.

You should seriously watch Gattaca, and then try to justify what you just said. In short:

Quote:

The story centers on the irony of the perfect Jerome failing to succeed despite being given every advantage while the imperfect Vincent transcends his deficiencies through force of will and spirit.

There is a ton of real world examples of will and spirit defeating genetics. Mind over matter.